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Hepatitis C is first target for new therapy

A revolutionary new kind of antiviral drug has raised hopes of treatments for a range of diseases, from cancer to heart disease.

The therapy attacks a recently discovered class of molecule called microRNAs (miRNA), and trials in monkeys have now proved the therapy safe and effective.

Sakari Kauppinen, a molecular biologist leading the drug’s development at the Danish firm Santaris Pharma, says the drug will be trialled first as a treatment for hepatitis C, while similar drugs could target cancer, diabetes and heart disease.

“It’s difficult to predict what’s going to happen in humans,” says Markus Stoffel, a molecular biologist at the Institute of Molecular Systems Biology in Zurich, who was not involved in the study. However, he says the result is an important and necessary demonstration of the potential of such drugs.

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Tiny targets

Discovered 15 years ago in roundworms, miRNAs are now known to control the expression of thousands of human genes. Scientists have linked the naturally-produced molecules both to development and to diseases, including numerous cancers and heart disease.

“MicroRNAs, we believe, are major new targets for drug action in the pharmaceutical industry. At the same time they represent a real breakthrough for molecular biology,” says Keith McCullagh, CEO of Santaris, which is based in Hørsholm.

Along the path from gene to protein, cells produce intermediary molecules called messenger RNAs (mRNA). The much shorter miRNAs latch onto mRNAs and shut down gene expression. In this way, any given sequence of miRNA might control the operation of hundreds of different mRNAs.

Researchers at Santaris previously muzzled a miRNA in mice to lower cholesterol. The drug targets miR-122, which controls cholesterol production. Called an antagomir, the drug is made of a sequence of nucleotides that bind tightly to miR-122, preventing the miRNA from controlling up to 450 genes.

Now, Santaris has proven that the drug effectively targets miRNA in monkeys. African green monkeys who received three shots of the drug saw their cholesterol levels drop up to 40% – an effect comparable to popular drugs used to treat high cholesterol, McCullagh says. The monkey’s cholesterol levels stayed down for about a month, before returning to normal.

Importantly, the drug caused no side effects in the monkeys. Their blood, livers, and kidneys all looked normal after the drug regimen.

An unmet need

The researchers used cholesterol as an indicator that the drug was effectively blocking miR-122, but their first target disease will be hepatitis C.

“Hepatitis C infection is the first disease we are going after with this compound,” Kauppinen says. Peter Sarnow, a collaborator at Stanford University in California, has shown that as well as the cholesterol-lowering effect, blocking miR-122 also prevents the hepatitis C virus from replicating in cells.

The virus infects 170 million people worldwide, according to the World Health Organization, and the current treatments work in fewer than half of patients. “It’s an unmet medical need,” Kauppinen says.

Santaris plans to launch safety trials in healthy human volunteers this year. If those tests go well they will begin a second round of studies, in patients infected with the virus.

“If this shows efficacy in hepatitis C phase 2 trials, we will push ahead very quickly with phase 3, and we might be able to bring it to market in five years,” McCullagh says.

Hurdles ahead

Other diseases might also be treated by blocking miRNAs, says Steffel.

“There are at least half a dozen miRNAs upregulated in cardiomyopathy, and when you silence them you protect the heart.”

In addition to hepatitis C, Santaris is looking to tackle blood cancers such as leukaemia, McCullagh says. Because the antagomir drugs are based on the sequence of a targeted miRNA, developing them is less complicated, compared to other drugs.

Getting approval is another matter. The novelty of the drugs could complicate their path to the market, McCullagh admits. For instance, regulators might require a lengthier follow-up to ensure safety. “This will be a first-in-man study for this class of drug,” he says.